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CASE REP O R T Open Access Failure of functional imaging with gallium-68- DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report Linsey U Gani 1 , Emily J Gianatti 1 , Ada S Cheung 1 , George Jerums 1 and Richard J MacIsaac 1,2* Abstract Introduction: The diagnostic efficacy of biochemical and imaging modalities for investigating the causes of Cushing’s syndrome are limited. We report a case demonstrating the limitations of these modalities, especially the inability of functional imaging to help localize the site of ectopic adrenocorticot ropic hormone secretion. Case presentation: A 37-year-old Arabian woman presented with 12 months of progressiv e Cushing’s syndrome- like symptoms. Biochemical evaluation confirmed adrenocorticotropic hormone -dependent Cushing’s syndrom e. However, the anatomical site of her excess adrenocorticotropic hormone secretion was not clearly delineated by further investigations. Magnetic resonance imaging of our patient’s pituita ry gland failed to demonstrate the presence of an adenoma. Spiral computed tomography of her chest only revealed the presence of a non-specific 7 mm lesion in her left inferobasal lung segment. Functional imaging, including a positron emission tomography scan using 18-fluorodeoxyglucose and gallium-68-DOTA-D-Phe1-Tyr3-octreotide, also failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Our patient was commenced on medical treatment with ketoconazole and metyrapone to control the clinical features associated with her excess cortisol secretion. Despite initial normalization of her urinary free cortisol excretion rate, levels began to rise eight months after commencement of medical treatment. Repeated imaging of her pituitary gland, chest and pelvis again failed to clearly localize a source of her excess adrenocorticotropic hormone secretion. The bronchial nodule was stable in size on serial imaging and repeatedly reported as having a nonspecific appearance of a small granuloma or lymph node. We re-explored the treatment options and endorsed our patient’s favored choice of resection of the bronchial nodule, especially given that her symptoms of cortisol excess were difficult to control and refractory. Subsequently, our patient had the bronchial nodule resected. The histological appearance of the lesion was consistent with that of a carcinoid tumor and immunohistochemical analysis revealed that the tumor stained strongly positive for adrenocorticotropic hormone. Furthermore, removal of the lung lesion resulted in a normalization of our patient’s 24-hour urinary free cortisol excretion rate and resolution of her symptoms and signs of hypercortisolemia. Conclusion: This case report demonstrates the complexities and cha llenges in diagnosing the causes of adrenocorticotropic hormone -dependent Cushing’s syndrome. Functional imaging may not always localize the site of ectopic adrenocorticotropic hormone secretion. * Correspondence: r.macisaac@unimelb.edu.au 1 Endocrine Centre and Department of Medicine, Austin Health and University of Melbourne, PO BOX 5444, Heidelberg West 3081, Victoria, Australia Full list of author information is available at the end of the article Gani et al. Journal of Medical Case Reports 2011, 5:405 http://www.jmedicalcasereports.com/content/5/1/405 JOURNAL OF MEDICAL CASE REPORTS © 2011 Gani et al; licensee BioMed Central Ltd. This is an Op en Acc ess articl e distribute d unde r the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction The diagnostic efficacy of biochemical a nd imaging modalities for localizing the anatomical site of ectopic adrenocorticotropic hormone (ACTH) secretion are lim- ited. Somatostatin receptor scintigraphy (SRS), using the ligand 111-indium-pentetreotide, has traditionally been the functional imaging technique used, but it’ suseful- ness has been questioned [1] . Recently, positro n emis- sion tomography (PET) scanning using gallium-68- DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) has been reported to be a superio r modality for detect ing neu- roendocrine tumors [2]. However, here we describe a case where this functional imaging technique fail ed to localize the site of ectopic ACTH secretion. Case presentation A 37-year-old Arabian woman was referred to our endo- crinology clinic with 12 months of progressive weight gain of 30 kg, hirsutism, acne, alopecia, lethargy, ame- norrhea and mark ed anxiety. An examination revealed features of Cushing’s syndrome with rounded face, buf- falo hump, abdominal striae and proximal muscle weak- ness. Investigations confirmed excess cortisol production. Her 24-hour urinary free cortisol excretion was 1870 nmol/day (normal range 40-4 50 nmol/day), her midnight saliv ary cortisol level was 121 nmol/L (normal range < 9 nmol/L) and after a 1 mg overnight dexamethasone suppression test her serum cortisol level was 597 nmol/L (expected value < 50 nmol/L). Her serum ACTH level was elevated at 55.8 and 55.1 ng/L on two separate occasions (normal range 7-63.2 ng/L), consistent with a diagnosis of ACTH-dependent Cush- ing’s syndrome. Magnetic resonance imaging (MRI) of her pituitary gland did not reveal the presence of an adenoma. LocalizingthesourceofexcessACTHsecretionwas challenging. Inferior petrosal sinus (IPS) sampling was difficult due to a left petrosal sinus anatomical variation. However, it demonstrated a central to peripheral ACTH gradient of less than three, consistent with ectopic ACTH secretion. This diagnosis was supported by fail- ure o f cortisol suppression (472 nmol/L) after an 8 mg overnight dexamethasone suppression test. Computed tomography (CT) of her chest, abdomen and pelvis only revealed a well circumscribed 7 mm left inferior basal lung segment lesion. This was reported to most l ikely represent a benign gran uloma or a small lymph node (Figure 1). Due to the wide range in sensitivity and specificity of thehighdosedexamethasonesuppression test (59-92% and 67-100%, respectively) and the inability to success- fully catheterize her left IPS, further dynamic biochem- ical tests were performed [3]. A five-hour intravenous dexamethasone test suppressed her serum cortisol level at five hours to less than 70% of basal values and a per- ipheral corticotrophin-releasing hormone (CRH) test showed a 58% increase in ACTH levels from baseline. Contrary to preceding results, these findings could be interpreted to suggest the presence o f a pituitary source for her excess ACTH secretion. However, PET scanning using 18-fluorodeoxyglucose (FDG) and galliu m-68- DOTATOC failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Serial CT scanning of her chest, abdomen and pelvis over 18 months failed to definitively localize a source of ectopic ACTH production. The well circumscribed 7 mm left i nferior basal lung segment lesion was reported as stable in size over this time. A repeat MRI of her pituitary gland once again did not reveal the presence of an adenoma. Given the failure of biochemical or imaging techni- ques to localize the site of excess ACTH secretion, med- ical therapy was initiated with keto conazole. However, combination treatment with metyrapone was required after eight months due to rising 24-hour urinary free corti sol levels and pr ogressive symptoms of weight gain, lethargy, depression and anxiety. D espite combination medical the rapy there was still a progressive rise in 24- hour urinary free cortisol levels(Figure2).Asaresult, our patient again developed florid symptoms of weak- ness, depression and anxiety which limited her daily activities and interpersonal relationships. Given the failure of medical therapy to control her symptoms, other potential treatment options were dis- cussed with our patient. These i ncluded progressing to bilateral adrenalectomy or resection of the lung lesion, whichwastheonlypossibleanatomical site of ectopic ACTH se cretion located so far. Unfortunately, the lung lesion was reported to be lying adjacent to the pericar- dium which negated a minimally invasive surgical Figure 1 Transverse image of a chest CT scan showing a small 7 mm inferobasal segment lesion (arrow) in the left lower lobe. Gani et al. Journal of Medical Case Reports 2011, 5:405 http://www.jmedicalcasereports.com/content/5/1/405 Page 2 of 4 approach to remove it. Despite this our patient still strongly favored proceeding to resection of the lung lesion even though this would require an open proce- dure. H ence, an open thoracotomy to remove the lung lesion was performed 18 months after her initial presentation. Histological examination of the resected nodule showed a 9 mm well circumscribed tumor surrounding a bronchus, with features consistent with a carcinoid tumor. Immunohistochemical analysis revealed that the tumor stained strongly positive for chromogranin, synaptophysin and ACTH. Postoperative recovery was uneventful and perioperative corticosteroid replacement was progressively weaned. Clinically, her symptoms of Cushing’s syndrome slowly abated. She achieved a nor- mal 24-hour urinary free cortisol excretion off all t reat- ment four months after surgery. Our patient remains well with no clinical or biochemical evide nce of cortisol excess seven months after her surgery. Discussion This case illustrates the difficulty in diagnosing a pitui- tary or an ectopic source of ACTH-dependent Cushing’s syndrome. A wide variability in the sensitivity and speci- ficity of current biochemical dynamic tests has been reported (Table 1). None of the current diagnostic tests are able to differentiate between pituitary and ectopic ACTH syndrome with 100% sensitivity and specificity. Thus there is a need for a combination of tests to help determine the cause of Cushing’s syndrome. Furthermore, functional imaging may not always assist in localizing an anatomical site of excess ACTH secretion (Table 2). In some instances, ectopic ACTH- secreting tumors can be detected by SRS using 111- indium-pentetreotide, or as highlighted in a recent case reported in this journal, with technetium-99 m- labelled octreotide acetate [4]. However, the sensitivity of SRS for detecting occult tumors that secrete ACTH only ranges from 30 to 53% [1]. In contrast, some pre- liminary reports have suggested that PET scanning using gallium-68-DOTATOC yields a higher detection rate of neuroendocrine tumors compared to SRS [2]. Despite this, the limitations of even t his technique to localize an ectopic source of ACTH secretion are high- lighted by this case. When all modalities fail to localize a source of ecto- pic ACTH, the role of clinical judgment plays a signifi- cant role. Ongoing monitoring of the patient, combined with a relevant discussion of risks and bene- fits of different therapeutic options led to a decision to proceed to removal of the small bronchial nodule. This nodule was subsequently confirmed to be an ACTH- secreting carcinoid tumor. Embarking on this decision despite there being no definitive preoperative confir- mationthatthenodulewasthesourceofherectopic ACTH production resulted inacureofourpatient’ s Cushing’s syndrome. Conclusion We have shown the limitations of the currently available diagnostic tools in differentiating pituitary or ectopic sources of ACTH-dependent Cushing’ ssyndrome. Furthermore, despite significant advances in radiological and nuclear medicine imaging modalities, the localiza- tion of the site of ectopic ACTH may still not be possible. Consent Written informed consent was obtained from the patient for publication of this case report and any Urinary Free Cortisol Excretion Rate ( nmol / d) Ketoconazole 200mg bd Ketoconazole 400mg bd Ketoconazole 400mg bd & Metyrapone 750 mg bd Surgery Figure 2 Pattern of 24-hour urinary free cortisol secretion (normal range: 25-360 nmol/day) in response to various treatment modalities. Note the horizontal axis is not to scale. Table 1 Reported sensitivity and specificity of commonly utilized dynamic biochemical diagnostic tests for determining the site of excess ACTH secretion Diagnostic Test Sensitivity Specificity Overnight high dose dexamethasone suppression test (8 mg) [3] 59-92% 67-100% IV dexamethasone suppression test [5] 95-100% 40-90% Ovine CRH stimulation test [5] 85-93% 85-90% IPS sampling (central: peripheral gradient) [6] 81-85% 90-100% Table 2 Reported sensitivity of current imaging modalities for localizing the site of ectopic ACTH secretion Imaging Modalities Sensitivity Specificity CT and MRI [7] 53 -74% n/a 111-indium pentetreotide SRS [1] 33-88% n/a 18-FDG PET scanning [8] 35-66% n/a Gallium 68-DOTATOC PET scanning [2] 82% n/a Gani et al. Journal of Medical Case Reports 2011, 5:405 http://www.jmedicalcasereports.com/content/5/1/405 Page 3 of 4 accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Acknowledgements We acknowledge the Austin Hospital’s thoracic surgical unit and its radiology department for their assistance in the management of this patient. Author details 1 Endocrine Centre and Department of Medicine, Austin Health and University of Melbourne, PO BOX 5444, Heidelberg West 3081, Victoria, Australia. 2 Department of Endocrinology and Diabetes, St Vincent’s Hospital and University of Melbourne, PO BOX 2900 Fitzroy 3065, Victoria, Australia. Authors’ contributions EG, AC and RM analyzed and interpreted the patient’s data and were involved in the patient’s care. LG was a major contributor to writing the manuscript. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Received: 23 February 2011 Accepted: 23 August 2011 Published: 23 August 2011 References 1. Torpy DJ, Chen CC, Mullen N, Doppmann JL, Carrasquillo JA, Chrousos GP, Nieman LK: Lack of utility of 111In-Pentreotide Scintigraphy in Localizing Ectopic ACTH Producing Tumors: Follow-Up of 18 Patients. J Clin Endocrinol Metab 1999, 84:1186-1192. 2. Khan MU, Khan S, El-Refaie S, Win Z, Rubello D, Al-Nahhas A: Clinical indications for gallium-68 positron emission tomography imaging. Euro J Surg Onc 2009, 35:561-567. 3. Aron DC, Raff H, Findling JL: Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab 1997, 82:1780-1785. 4. Esfehani AF, Chavoshi M, Noorani MH, Saghari M, Eftekhari M, Beiki D, Fallahi B, Assadi M: Successful application of technetium-99 m-labeled octreotide acetate scintigraphy in the detection of ectopic adrenocorticotropin-producing bronchial carcinoid lung tumor: a case report. 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Pacak K, Ilias I, Chen CC, Carrasquillo JA, Whatley M, Nieman LK: The role of [18F] fluorodeoxyglucose positron emission tomography and [111 In]- diethylenetriaminepentaacetate-D-Phe-pentreotide scintigraphy in the localization of ectopic adrenocorticotropin-secreting tumors causing Cushing’s syndrome. J Clin Endocrinol Metab 2004, 89:2214-2221. doi:10.1186/1752-1947-5-405 Cite this article as: Gani et al.: Failure of functional imaging with gallium-68-DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report. Journal of Medical Case Reports 2011 5:405. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Gani et al. Journal of Medical Case Reports 2011, 5:405 http://www.jmedicalcasereports.com/content/5/1/405 Page 4 of 4 . CASE REP O R T Open Access Failure of functional imaging with gallium-68- DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone. here we describe a case where this functional imaging technique fail ed to localize the site of ectopic ACTH secretion. Case presentation A 37-year-old Arabian woman was referred to our endo- crinology. time. A repeat MRI of her pituitary gland once again did not reveal the presence of an adenoma. Given the failure of biochemical or imaging techni- ques to localize the site of excess ACTH secretion,